Association between dexamethasone exposure and visually significant cataracts in multiple myeloma
Authors: Rahul Banerjee, Jorge Arturo Hurtado Martínez, Patricia Alejandra Flores Pérez, Nolan Porras, Jay Hydren, Jennifer M. Ahlstrom, Parisa Taravati, Andrew J. Cowan
Journal: American Journal of Hematology (2023)

Eye health in patients with myeloma. Newer regimens have continued to improve outcomes in multiple myeloma (MM). For many such regimens, dexamethasone (often 20–40 milligrams weekly) is continued alongside other anti-MM agents until progression. A link between systemic dexamethasone and ocular cataracts was first established decades ago, likely due to corticosteroid-related metabolic or oxidative changes within the lens.1-4 Despite the ubiquity of dexamethasone in MM regimens, however, relatively few studies have investigated its association with ocular toxicities in MM. In one claims analysis, the prevalence of ocular comorbidities in MM rose with each subsequent line of therapy (LoT) as compared to newly diagnosed MM.5 Potential mechanisms for this finding include continued dexamethasone, advancing age, and perhaps chronic paraprotein-mediated damage to the lens.6, 7 As a first step toward characterizing the specific impact of dexamethasone on ocular comorbidities, we used patient-reported and Electronic Medical Record (EMR)-derived data to analyze relationships between dexamethasone exposure, patient-reported cataract incidence, and patient-reported cataract severity. We analyzed patient-reported data from users of the HealthTree Cure Hub for MM, an online platform promoted to patients with MM residing in the United States (US) through emails, social media, and community events. As of December 2022, 11 356 patients with MM have created a Cure Hub account. In addition to educational materials and discussion forums, patients can optionally answer questions about previous LoT and what side effects they developed. The platform also optionally allows patients to authorize linkage of their treating center's EMR to their survey responses for use in deidentified research. We conducted a targeted analysis of patients on the Cure Hub platform who had recalled first developing cataracts with any LoT, including their current LoT. All patients who reported cataracts were asked to rate their cataracts at the time of initial presentation on a 1–5 scale of severity: (1) hardly noticeable; (2) uncomfortable but manageable; (3) disruptive; (4) severely disruptive; and (5) unmanageable requiring treatment discontinuation. When patients reported that cataracts had developed with a given LoT, we estimated the number of cycles before cataract onset by calculating the total number of months where the patient had been on any dexamethasone-containing regimen (excluding months without any corticosteroids, for example, lenalidomide maintenance). Within the LoT where cataracts were first reported, we approximated the actual date of cataract incidence as the median date between LoT initiation and discontinuation (or, for patients still on that LoT, the median date between LoT initiation and survey completion). For uniformity, we converted days of dexamethasone exposure into 28-day cycles. For the subset of patients who had authorized EMR linkage at the time of survey completion, we reviewed their dexamethasone prescriptions to identify the total number of dexamethasone-containing cycles, total milligrams (mg) dexamethasone prescribed across all cycles, and median mg dexamethasone per week across all dexamethasone-containing cycles. We conducted time-to-event survival analyses to conduct the cumulative risk of cataracts based on the number of cycles of exposure to dexamethasone. Ordinal logistic regression and correlation analyses were performed to evaluate the association between dexamethasone exposure and cataract severity. The parent protocol for the use of the Cure Hub for de-identified secondary analyses was reviewed and declared exempt by the WCG Institutional Review Board. Of 231 patients who reported having developed cataracts following the initiation of MM therapy, respondents were balanced between genders (43% male, 57% female) but were predominantly White (85%). The median age at cataract onset was 65 years [interquartile range (IQR) 61–68], and most patients were on their first LoT (78%, n = 182) or second LoT (17%, n = 40) at the time of cataract onset. Cataract severity (on a 1–5 Likert scale) was rated as hardly noticeable by 23%, uncomfortable by 29%, disruptive by 36%, severely disruptive by 11%, and requiring treatment discontinuation by 1%. Time-to-event analyses (Figure 1) demonstrated that, of patients who did develop cataracts, 36% (n = 83) did so within 6 cycles of dexamethasone-containing regimens while 48% (n = 111) did so within 12 cycles. We then performed more detailed analyses of the 97 patients (42% of all respondents) who had pre-authorized EMR linkage at the time of survey completion. Compared to the larger population of respondents, this subset of 97 patients had similar demographic characteristics apart from ethnicity (Table S1). Of these 97 patients, the median total dexamethasone dose from first-line treatment initiation to the time of cataract development was 1020 mg (IQR 520–2000 mg), which corresponded to a median dose of 40 mg (IQR 20–40 mg) per week. Ordinal regression analyses demonstrated a significant association between total mg of dexamethasone exposure and cataract severity, with a coefficient estimate (ce) of .255, p = .047. Among patients who rated their cataracts as severely disruptive or unmanageable (4 or higher on a 1–5 Likert scale), median total dexamethasone exposure was 1907 mg versus 788 mg for those who rated their cataract severity as hardly noticeable (1 on a 1–5 Likert scale). However, age at cataract onset (ce .004, p = .817), median dexamethasone dose per cycle (ce −.004, p = .189), and total number of dexamethasone-containing cycles (ce −0.016, p = .155) did not show significant relationships with cataract severity. In summary, we analyzed patient-reported data around cataract timing and reported severity for 231 patients living with MM. Of patients who newly developed cataracts following their MM diagnosis, over a third did so within 6 months of exposure to dexamethasone. We also conducted a more detailed analysis of dexamethasone dosing in patients who had authorized EMR linkage to their responses. In this subset of almost 100 patients, we found that total milligrams of dexamethasone exposure longitudinally—but not milligrams per cycle or total number of cycles—was a significant predictor of cataract severity. Indeed, patients who rated their cataracts as severely disruptive or unmanageable had over twice the total dexamethasone exposure as those who rated their cataracts more mildly. Our findings serve as the starting point for prospective research into the ocular health of patients with MM with an emphasis on dexamethasone dosing. Given the modest nature of our cross-sectional analysis, our study limitations warrant upfront discussion. Due to the ubiquity of corticosteroids in MM treatment regimens, we did not have a control arm of patients who were unexposed to dexamethasone during therapy. Similarly, although patients identified the start and end dates of the LoT during which they first developed cataracts, we were not able to identify precisely when cataracts developed during that LoT. For our second set of analyses involving detailed dexamethasone dosing, other potential confounders for cataract development (for example, lens damage from high paraprotein levels)2 could not be assessed. Compared to the US distribution of patients with MM,8 our respondents were younger, more likely to be female, and less likely to be from racial minorities. Selection bias in terms of patients who were willing to create a Cure Hub account and participate in this survey may also limit the generalizability of our findings. Nevertheless, our study is noteworthy in that total longitudinal dexamethasone dose (but not total time on dexamethasone) was a significant predictor of cataract severity. Cataracts are very prevalent in relapsed MM, a fact underscored by baseline ophthalmological exams in studies of belantamab mafodotin. In a pooled analysis of the DREAMM-2 trial among patients who had received at least three prior LoT (median ages 65–67 at baseline), 60% of patients were found to have cataracts on ophthalmologic exams before their first dose of belantamab.9 This high prevalence is related to several factors, including advancing age itself as a risk factor for cataract development.10 Our research focused more specifically on patient-reported cataracts, almost half of which were rated as uncomfortable or disruptive when they were diagnosed. Visually significant cataracts can impair patient quality of life as well as the practicalities of MM care, for example, one's ability to drive to the clinic for infusions. Future survey-based studies of ocular health in plasma cell disorders, enrolling both patients with MM as well as age-matched controls with MM precursor conditions where weekly dexamethasone is not used, are actively in development. These studies will also investigate the risk of corticosteroid-induced glaucoma, another ophthalmologic complication that carries a potential risk of irreversible vision loss. More broadly, the importance of dexamethasone in MM after its initial role in cytoreduction and infusion reaction prophylaxis remains unclear. Among frailer patients, scheduled discontinuation of dexamethasone during first-line therapy does not compromise efficacy.11 There are already many reasons to consider dexamethasone dose reduction in MM based on toxicities that patients and physicians recognize rapidly, for example, insomnia or hyperglycemia. Our study demonstrates that dexamethasone may also accelerate the development of visually significant cataracts, an adverse event that may develop more insidiously. Given the uncertain long-term contribution of dexamethasone to most MM regimens, our findings suggest that reducing dexamethasone exposure after the first few cycles could be considered in all patients with MM regardless of age or frailty. The authors acknowledge the patients who participated in this study. Jennifer M. Ahlstrom Patient advocacy committee: Pfizer, BMS, Janssen, Takeda Oncology, and Sanofi. JRH receives research funding from Adaptive Biotechnologies, Sanofi, GlaxoSmithKline, Regeneron, Janssen and Takeda. Rahul Banerjee: Consultancy: BMS, Janssen, Pfizer, Genentech/Roche, Sanofi Pasteur, SparkCures; Research Funding: Pack Health. Jennifer M. Ahlstrom: Consultancy: Pfizer, BMS, Janssen, Takeda, and Sanofi. Andrew J. Cowan: Consultancy: BMS, Adaptive Biotechnologies; Research Funding: Adaptive Biotechnologies, Harpoon, Nektar, BMS, Janssen, Sanofi, Abbvie. Data are available upon reasonable request by emailing the corresponding author ([email protected]). Table S1. Baseline demographics. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.